Comprehensive evaluation of otorhinolaryngological symptoms in COVID-19 patients

Introduction The aim of this study is to comprehensively evaluate the incidence and natural course of otorhinolaryngological symptoms of COVID-19 infection and its relations to each other and patient’s demographics. Methods This is a prospective study conducted on symptomatic adult patients proven to be infected with COVID-19. Detailed history was taken from each patient including onset of symptoms. Symptoms were followed up tightly. We focus on otorhinolaryngological (ORL) symptoms and their duration and onset in relation to other symptoms. Data were collected and analyzed in detail. Results Six-hundred eighty-six patients were included in the study, their age ranged from 19-75 years old, and of them 55.1% were males. Cough was found in 53.1% of cases followed by sore throat in 45.8%, anosmia/ hyposmia in 42.3%, headache in 42%, rhinorrhea in 19.5%, dry mouth in 7.6%, globus in 6.1%, epistaxis in 4.4%, and hearing loss in 0.6%. In non-ORL symptoms, fever was found in 54.2%, malaise in 55.1%, dyspnea in 49.3%, and diarrhea in 27.2%. The first symptom was anosmia in 15.7% of cases, sore throat in 6.1 %, cough in 7.9%, and headache in 13.4% of cases. Fever was the first symptom in 22.7%, malaise in 25.1%, and diarrhea in 6.4%. Headache occurred for 5.5 ± 2 days, anosmia/hyposmia 3 to > 30 days, sore throat 4.1 ± 1.2 days, rhinorrhea 4.3 ± 1.1, cough 7.4 ± 2.5 days, fever 4.7 ± 2 days, and malaise 6.5 ± 2.4 days. The cluster of COVID-19-related symptoms showed nine principal components. Conclusion Otorhinolaryngological symptoms are main symptoms in COVID-19 infection, and they should be frequently evaluated to detect suspected cases especially in pauci-symptomatic patients and to properly manage infected patients. Supplementary Information The online version contains supplementary material available at 10.1186/s43163-022-00263-5.


Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, at the end of 2019 [1]. In February 2020, it was officially called "COVID-19" by the WHO [2]. It became pandemic and has disastrous impact on health care and economic systems around the world. As of 20th April 2021, the WHO reports that 140 million people have been diagnosed with COVID-19 worldwide, with 3 million deaths, including 220 countries and territories. And mostly, the disease will continue to spread due to the reduction in strict measures [2,3].
Seven coronaviruses are known to transmit to humans including SARS-CoV-2, SARS-CoV, and MERS-CoV (Middle East respiratory syndrome coronavirus) [4]. Growing evidence confirmed the nasal cavity is a vital area susceptible to SARS-CoV-2 infection. Researchers compared the pathology and virology of SARS-CoV-2, SARS-CoV, and MERS-CoV. They confirmed that these

Open Access
The Egyptian Journal of Otolaryngology pathogenic coronaviruses have different mainly pathogenic sites: SARS-CoV-2 (nose and throat), SARS-CoV (lung), and MERS-CoV (type-2 pneumocytes). Viral loads in the patient's nasal cavity were higher than the viral loads in the pharynx, both symptomatic individuals and asymptomatic ones, hinting the nasal cavity as the first gateway for the initial infection [5,6]. COVID-19 symptoms are very similar to seasonal flu with the most common symptoms of fever, cough, shortness of breath, malaise, muscle aches, sore throat, headache, and tiredness, loss of taste, and or smell [7]. COVID-19 could be manifested by several symptoms, ranging from asymptomatic/mild symptoms to severe illness and death [8]. ENT manifestations are not uncommon symptoms of COVID-19, especially in mild or moderate form of the disease [9].
Mapping the symptoms and percentages of the disease will assist to discover COVID-19 disease more and create more effective treatment protocols. The general symptoms were discussed in detail in the literature, but to the best of our knowledge, there is a gap in detailed research on ENT manifestations in COVID-19 in the literature. So, here we collect the data from 686 patients confirmed to be COVID-19-positive by PCR, and this is the largest and most detailed case series study in the literature about this topic.

Methods
This prospective study was conducted at the Ain Shams University Specialized Hospital at El-Obour City (assigned as a quarantine hospital during the pandemic for COVID-19 patients) from 1st May 2020 to 15th July 2020. This study included symptomatic adult patients proven to be infected with COVID-19 by PCR in nasopharyngeal swab. Exclusion criteria were asymptomatic patients, patients with mental or physical defects hindering communications, and patients with previous significant upper airway surgeries. Severely infected patients, who were admitted to intensive care unit, were excluded from the study. Lost patients in follow-up were excluded from the study. Detailed history was taken from each patient personally by physicians or nurses completing sheets including demographic data, risk factors for COVID-19, comorbidities, and onset of symptoms. Symptoms were followed up tightly until complete recovery, or either patient was hospitalized or discharged for home isolation (followed by phone call). We focus on otorhinolaryngological (ORL) symptoms and their duration and onset in relation to other symptoms. ORL symptoms included in our study were cough, sore throat, anosmia, headache, nasal discharge, nasal obstruction, dysphagia, postnasal discharge, expectoration, dry mouth, earache, globus, vertigo, epistaxis, sneezing, tinnitus, facial pressure, otorrhea, stridor, deafness, neck swelling, and facial weakness. Non-ORL symptoms were fever, malaise, myalgia, diarrhea, and dyspnea.

Statistical methods
Data were analyzed using IBM© SPSS© Statistics version 26 (IBM© Corp., Armonk, NY). Continuous numerical variables are presented as mean and standard deviation and categorical variables as counts and percentages.
We conducted maximum likelihood principal component analysis (PCA) on the 27 symptoms that we screened for. The Kaiser-Meyer-Olkin (KMO) measure of sampling adequacy and Bartlett's test of sphericity were used to examine suitability of data for component analysis. A KMO value of ≥ 0.6 and a P-value < 0.05 for the Bartlett's test were identified as criteria for sampling adequacy and feasibility of PCA.
Initial component extraction was based on a cutoff criterion of eigenvalue greater than 1. Besides, a scree plot was examined, and all components with eigenvalues situated on the sharp descent of the plot before it levelled out were retained. Based on the results of initial factor extraction, 9 principal components were rotated using an orthogonal (Varimax) rotation solution.
Two-sided P-values < 0.05 are considered statistically significant.

Results
There were 686 patients included in our study aged 19 to 75 years old with 72% of them at or above 50 years old. A total of 65% were symptomatic before confirmation of diagnosis by PCR. A total of 82% were infected mildly (no need for hospitalization) ( Table 1). Cough, sore throat, anosmia, and headache were the most prevalent ORL symptoms (Table 2) (Fig. 2), while non-ORL symptoms were presented as follows: malaise 55.1%, fever 54.2%, dyspnea 49.3%, myalgia 32.7%, and diarrhea 27.2% (Fig. 1).
Headache presented as first symptom in 13.4% and anosmia in 15.7%. Sore throat presented as second symptom in 18.4%, cough in 11.1%, anosmia in 10.8%, and nasal discharge in 9% (Table 3) In non-ORL symptoms, fever presented as first symptom in 22.7% and second in 13.1%. Malaise presented as first symptom in 25.1% and second in 10.2%. Dyspnea presented as third symptom in 12.5% and fourth in 11.4%. Diarrhea presented as first symptom in 6.4% (Figs. 2,3,4,5).
By applying the principal component analysis for the cluster of COVID-19-related symptoms, it showed that groups of symptoms tend to be together. Group 1 symptoms are fever, headache, malaise, sore throat, cough, and dyspnea. Group 2 symptoms are nasal obstruction, nasal discharge, anosmia, etc. (Supplemental Table 2).
In terms of the association between the clinical symptoms and patient factors, as regards age, there was a statistically significant association between younger age and fever and cough. As regards gender, there was a statistically significant association between male gender and epistaxis. As regards smoking, there was a statistically significant association between smoking and headache, malaise, and sore throat. As regards asthma, there was a statistically significant association between asthma and malaise and post-nasal discharge. As regards diabetes mellitus, there was a statistically significant association between DM and fever, malaise, sneezing, and anosmia. As regards COPD, there was a statistically significant association between COPD and nasal obstruction, nasal discharge, epistaxis, dysphagia, and expectoration (Supplemental Table 3)
In terms of the chronological order of ORL symptoms, anosmia/ hyposmia was the first symptom in 15.7% of cases, second in 10.8%, and third in 5.2%. Sore throat was the first symptom in 6.1% of cases, second in 18.4%, and third in 5.5%. Cough was the first symptom in 7.9% of cases, second in 11.1%, third in 14.3%, and fourth in 11.7%. Headache was the first symptom in 13.4% of cases, second in 10.8%, and third in 6.1%. Rhinorrhea was the second symptom in 9% of cases. Postnasal discharge was the third symptom in 5.8% of cases. In non-ORL symptoms, fever presented as first symptom in 22.7% and second in 13.1%. Malaise presented as first symptom in 25.1% and second in 10.2%. Dyspnea presented as third symptom in 12.5% and fourth in 11.4%. Diarrhea presented as first symptom in 6.4%.
Principal component analysis for the cluster of COVID-19-related symptoms shows 9 principal components. Fever, headache, malaise, sore throat, cough, and dyspnea formed one component. Nasal obstruction, rhinorrhea, postnasal discharge, and anosmia/hyposmia formed one component. Dry mouth and myalgia formed one component. Dysphagia, diarrhea, and globus formed one component. Vertigo, tinnitus, and hearing loss formed one component.
Ozcelik et al. found that cough and dyspnea were more common in elder patients (over 60 years), and that anosmia/hyposmia, headache, and sore throat were common in younger patients and in female. Anosmia/hyposmia and sneezing were more common in patients with allergic rhinitis, while headache was more common in hypertensive and diabetic patients. Dyspnea was more common in patient with chronic chest diseases [18].
In our study, we found a statistically significant association between younger age and fever cough and association between male gender and epistaxis. As regards smoking, there is a statistically significant association between smoking and headache, malaise, and sore throat and a statistically significant association between asthma and malaise and post-nasal discharge. As regards diabetes mellitus, there is a statistically significant association between DM and fever, malaise, sneezing, and anosmia. As regards COPD, there was a statistically significant association between COPD and nasal obstruction, nasal discharge, epistaxis, dysphagia, and expectoration.
Limitations of this study are that 72% of included patients were at or above 50 years old, and that we could not follow-up symptoms in severely infected patients in intensive care unit.

Conclusion
Otorhinolaryngological symptoms are main symptoms in COVID-19 infection, and they should be frequently evaluated to detect suspected cases especially in pauci-symptomatic patients and to properly manage infected patients.